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This Article Full Text Full Text (PDF) All Versions of this Article: 288/2/L359    most recent 00292.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Wang, Q. Articles by Doerschuk, C. M. Search for Related Content PubMed PubMed Citation Articles by Wang, Q. Articles by Doerschuk, C. M.

MKK3 and -6-dependent activation of p38 MAP kinase is required for cytoskeletal changes in pulmonary microvascular endothelial cells induced by ICAM-1 ligation

¹Division of Integrative Biology, Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio; ²ISIS Pharmaceuticals, Incorporated, Carlsbad; and ³Pfizer, Incorporated, La Jolla, California

Submitted 4 August 2004 ; accepted in final form 25 October 2004

Previous studies demonstrated that neutrophil adherence induces ICAM-1-dependent cytoskeletal changes in TNF--treated pulmonary microvascular endothelial cells that are prevented by a pharmacological inhibitor of p38 MAP kinase. This study determined whether neutrophil adherence induces activation of p38 MAP kinase in endothelial cells, the subcellular localization of phosphorylated p38, which MAP kinase kinases lead to p38 activation, which p38 isoform is activated, and what the downstream targets may be. Confocal microscopy showed that neutrophil adhesion for 2 or 6 min induced an increase in phosphorylated p38 in endothelial cells that was punctate and concentrated in the central region of the endothelial cells. Studies using small interfering RNA (siRNA) to inhibit the protein expression of MAP kinase kinase 3 and 6, either singly or in combination, showed that both MAP kinase kinases were required for p38 phosphorylation. Studies using an antisense oligonucleotide to p38 demonstrated that inhibition of the protein expression of p38 1) inhibited activation of p38 MAP kinase without affecting the protein expression of p38; 2) prevented phosphorylation of heat shock protein 27, an actin binding protein that may induce actin polymerization upon phosphorylation; 3) attenuated cytoskeletal changes; and 4) attenuated neutrophil migration to the EC borders. Thus MAP kinase kinase3- and 6-dependent activation of the -isoform of p38 MAP kinase is required for the cytoskeletal changes induced by neutrophil adherence and influences subsequent neutrophil migration toward endothelial cell junctions.

tumor necrosis factor-; neutrophil; actin; inflammation; mitogen-activated protein kinase kinase 3/6; intercellular adhesion molecule

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